David S. Hilzenrath, Project on Government Oversight: March 19, 2021
On December 10, as the Food and Drug Administration (FDA) considered issuing its first emergency authorization for a vaccine to combat the pandemic, the agency asked a committee of outside advisors to vote on this question:
“Based on the totality of scientific evidence available, do the benefits of the Pfizer-BioNTech COVID-19 vaccine outweigh its risks for use in individuals 16 years of age and older?”
The FDA’s wording of the question was read aloud, debated, repeated, and left unchanged, and the official minutes of the meeting record that the vote of 17 to 4 with one abstention was “based on the totality of scientific evidence available.”
The next day, the FDA issued the authorization.
But for the FDA, what was the totality of the evidence?
How much did it know, and what if anything was it leaving unsaid?
Ten days after the FDA authorized the vaccine for use in the United States, the agency’s European Union counterpart greenlighted the shot’s use in Europe. The European Medicines Agency (EMA) set a markedly different example of disclosure on a subject the FDA addressed only minimally in public: quality control in the manufacture of the vaccine.
The European regulator laid out its findings about quality control in a 140-page report. It disclosed concerns that had arisen during the course of its review—some of which at one point had been classified as “Major Objections”—and explained how they had been addressed. It emphasized the limits of what it knew, and it said additional data was needed.
That included information on key characteristics of the vaccine.
“The characterisation and control of active substance and finished product are limited in relation to critical quality attributes and impurities,” the EMA said.
One of the issues the European regulator flagged: the possibility that aberrations in the vaccine could lead to “unwanted immunological events.”
The EMA said the risk of that happening was “considered low.”
The European regulator concluded that issues it spotlighted shouldn’t stand in the way.
“The benefits to public health of the immediate availability outweigh the risks inherent in the fact that additional data are still required,” it said.
“Given the emergency situation, it is considered that the identified uncertainties can be addressed post-authorisation,” it said.
In its December 21 assessment report, the European regulator presented information not to be found in the briefing paper the FDA gave members of the FDA’s vaccines advisory committee before its December 10 public meeting, not discussed at the meeting, and not disclosed in the public version of the memorandum in which the FDA explained its assessment of the vaccine.
The EMA’s public assessment described impurities that had been observed, analyzed, and ultimately found acceptable. It discussed inconsistencies between batches, another issue ultimately addressed to the EMA’s satisfaction.
Much of the EMA’s account pertained to the presence in the vaccine of irregular forms of the vaccine’s key component—a genetic material called mRNA—and levels of “RNA integrity.”
The report also noted the detection of something anomalous involving lipids, a fatty substance used to coat the mRNA. It said lipid-related impurities had been identified in recently produced finished product batches. It also said “particulate matter” had been observed in the vaccine.
FDA advisory committee members interviewed by the Project On Government Oversight (POGO) said they were unaware of that background information on the vaccine.
In granting its authorization, the European regulator dictated a plan to address remaining uncertainties over the ensuing months. It imposed what it called “specific obligations” on the manufacturer.
The required follow-ups included, for example, introducing an appropriate strategy for controlling lipid-related impurities, further analyzing RNA integrity, and providing more information on the method used to assess the vaccine’s potency.
“The quality of this medicinal product, submitted in the emergency context of the current (COVID-19) pandemic, is considered to be sufficiently consistent and acceptable subject to the specific obligations abovementioned,” the EMA summarized.
It is unclear whether the FDA was dealing with more information, less information, or the same information as its European counterpart when it granted its emergency use authorization (EUA).
What is clear is that it said less publicly.
Avoiding the Topic
The FDA said it was being transparent.
“Today’s meeting … continues FDA’s commitment to an expedited review process that is transparent, scientifically sound and data driven,” Dr. Doran Fink, deputy director for clinical review in an FDA division that evaluates vaccines, said toward the opening of the December 10 advisory committee meeting.
FDA officials walked the committee through extensive clinical trial data on the safety and effectiveness of the Pfizer-BioNTech vaccine.
But, as the committee considered whether to endorse emergency authorization of the still-experimental product, quality control received only perfunctory discussion. The FDA seemed determined to avoid the topic.
“FDA has reviewed the manufacturing quality and consistency data for the Pfizer-BioNTech vaccine and found it adequate to support emergency use authorization of the vaccine,” Fink, one of the lead FDA briefers, told the committee.
Dodging the Question
The bar for an FDA emergency use authorization is lower than the bar for FDA approval or licensure. But, as a practical matter, in the case of the first COVID-19 vaccine to receive the FDA’s blessing, the emergency action is almost tantamount to approval. It provides all the authority needed to immunize everyone age 16 and up, potentially for the duration of the current public health emergency.
Diana Zuckerman, president of the nonprofit National Center for Health Research, zeroed in on FDA statements that manufacturing quality and consistency data was adequate to support an emergency use authorization.
“My gut reaction is that it’s damning with faint praise to say something is adequate for an EUA, for 2 reasons,” Zuckerman said by email.
“Saying something is adequate is a low bar—shouldn’t the standard be that evidence is persuasive? Or at least ‘good’?” Zuckerman wrote. “The FDA’s standards for an EUA are acknowledged to be quite a bit lower than the standards for approval, so being adequate for an EUA is an especially low bar,” she added.
Authorization isn’t the last word. The system includes subsequent lines of defense for the public.
As with other vaccines, the FDA-approved instructions to people administering the shots call for them be on the lookout for signs of trouble.
“Inspect the vaccine in the vial,” the instructions say. “The vaccine will be an off-white suspension. Do not use if vaccine is discolored or contains particulate matter.”
The instructions count on people administering the vaccine to strike a careful balance. “Gently invert the vial . . . 10 times to mix,” they say. The instructions also say, “Do not shake.” That direction is underlined.
POGO asked the FDA to explain the reason for that instruction and what could happen if the vaccine is shaken before it’s injected. The FDA declined to answer and said to ask Pfizer.
Pfizer’s Danehy said the company included the instruction “to maintain the integrity of the vaccine.” The company wouldn’t say what could result if the vaccine is shaken.
To read the entire report, click here https://www.pogo.org/investigation/2021/03/avoiding-the-subject-on-pfizer-vaccine-quality-control-fda-says-less-than-european-counterpart/